Exacerbation of chronic obstructive pulmonary disease (COPD) contribute to most of the morbidity, mortality and health care costs associated with this important disease. We have previously shown that some patients with COPD are particularly susceptible to exacerbations whom we termed frequent exacerbators. These patients experience increase airway inflammation and faster FEV1 decline. However, the basis of this susceptibility to COPD exacerbation is not clear. This study will test the hypothesis that increased susceptibility to respiratory viral infections, particularly human rhinovirus (HRV), results in more frequent exacerbations and may be genetically determined. The proposal will address the following important questions: 1. Do exacerbations associated with respiratory viruses occur more commonly in frequent than infrequent exacerbators. 2. Are respiratory viral exacerbations more severe, with greater inflammation, leading to faster FEV1 decline? 3. Is ICAM-1, the major receptor site for human rhinovirus binding on epithelial cells, upregulated in patient with frequent exacerbators? 4. Are there any genotype differences in the ICAM-1, IL-6 and IL-8 genes between frequent and infrequent exacerbators that could account for the increased susceptibility to COPD exacerbation? 200 COPD patients mainly from the East London COPD cohort, stratified into two groups using existing data by exacerbation frequency, together with 100 normal controls matched for age, gender and smoking history, will be monitored for 2 years. Exacerbations will be sampled for respiratory viruses at exacerbations. FEV1 will be routinely monitored. Bronchial and nasal biopsies will be taken for cell culture and determination of slCAM-1, IL-6 and IL-8 production, and ICAM-1 surface expression. The inflammatory markers slCAM-1, IL- 6 and IL-8.will be measured in sputum and nasal lavage samples in the stable state and at exacerbation. Exacerbation frequency, rhinovirus exacerbation frequency and the inflammatory markers will be related to specific genetic ICAM-1, IL-6 and IL-8 polymporphisms. Results from this study will inform on the mechanisms underlying increased susceptibility to COPD exacerbation, and will be of immense importance for the development and targeting of new therapeutic strategies, either to prevent exacerbations or reduce their severity.